What responds sympathetically and is attached to bronchial smooth muscle, epithelium, glands and mast cells?

B2 adrenoceptors

What does binding of noradrenaline to B2 adrenoceptors do?

What does parasympathetic innervation of the airways do?

Parasympathetic activity is normally dominant in maintaining smooth muscle tone in the airways. Muscarinic Receptors are present on airway and vascular smooth muscle and glands. The M3 Receptor is pharmacologically the most important.

16

What are the three main categories of asthma pathophysiology in affected tissues

What are the five different remodelling factors which occur in Asthma

What is the early phase response in asthma?

In allergic asthma, initial response to allergen provocation is due to interaction with mast cell fixed IgE, resulting in histamine release and other potent spasmogens -> Bronchospasm

21

What occurs in the asthmatic late phase response?

Co-release of a range of mediators and chemotaxins activate a complex immune system response that brings leucocytes to the area. This sets off a further chain of event leading to exacerbated bronchospasm and congestion due to:o Epithelial damage Increased exposure of the sensory irritant receptors, further exacerbating bronchial hyperactivity and sensitivityo Thickening of the basement membraneo Oedemao Mucus production

22

Define bronchial hyperesponsiveness

exaggerated bronchoconstrictor response to direct pharmacological stimuli such as histamine, or indirect stimuli such as exercise

23

List the major drugs used to treat asthma

Short and long acting B2 agonistsMethylxanthinesMuscarinic receptor antagionists

24

What is the mechanism of action of B2 agonists in the treatment of asthma (molecular mechanism plz, + both mechanisms)

β2 agonists act on the β2 receptors found on bronchial smooth muscle. The receptors are coupled to Gs Proteins, which cause an increase in cAMP and consequent decrease in intracellular [Ca2+]. This reduces the activity of myosin light chain kinase and thus muscle contraction.

Additionally, the decrease in intracellular Ca2+ will also and increase Ca2+ activated K+ currents, thus hyperpolarising muscle cells further and augmenting bronchodilation.

25

How are B2 agonists administered?

β2 Agonists are administered by inhalation in aerosol, powder or nebulised form and can also be administered intravenously. Deposition within the pulmonary tract is related to particle size, with 1-5microns being optimal.

26

What happens to the majority of drug in asthma?

However, the majority of the drug (up to 90% depending on the inhaler device) is deposited in the upper airway and/or swallowed before being removed by the liver.

Give three adverse drug reactions of asthma

What drug intercations are there with B2 agonists?

o β-blockers such as Propranolol, which bind to both β1 and β2 receptors

31

Name the class of drugs which antagonise adenosine receptors

Methylxanthines

32

Name two methylxanthines

 Theophylline Aminophylline

33

What are the indications for methyxanthines?

 Status asthmaticus COPD

34

What are the two adverse drug reactions to methylxanthines?

Psychomotor agitationTachycardia

35

What does methylxanthines do?

Antagonise adenosine receptors

36

When would methylxanthines be used?

As 3rd or 4th lines asthma treatments

37

What is the mechanism of muscarininc receptor antagonists?

 Bind to and antagonise M3 cholinergic receptors on bronchial smooth muscle. This blocks the constricting effect of Ach and also inhibits mucus secretion.

38

Give two examples of muscarininc receptor antagonists

 Ipratropium bromide Tiotropium bromide

39

What are the indications for muscarinic receptor antagonist treatment?

 Ipratropium bromide Tiotropium bromide

40

Why are there few adverse drug reactions involved in muscarinin receptor antagonists?

 Not well absorbed through the lungs, avoiding major systemic ADRs Dry mouth

41

Outline the pharmacology of glucocorticoids

Like all steroid hormones, corticosteroids exert their effect via Nuclear Receptors. These receptors are found in the cytoplasm, complexed with heat shock proteins. Following the diffusion (or possibly transport) of their ligand into the cell and high-affinity binding, these receptors form a Homodimer with another ligand-receptor complex and translocate to the nucleus.

42

What do glucocorticoids do in the nucleus

In the nucleus, the steroid-receptor complex homodimers can Transactivate or Transrepress genes by binding to Positive or Negative Hormone Response Elements. Large numbers of genes can be regulated in this way by a single ligand. Therapeutic effects of changes in gene expression may only be apparent some hours after administration.

43

How do glucocorticoids express an anti-inflammatory effect?

Glucocorticoids have a profound generalised inhibitory effect on inflammatory response. This is mediated via reduced production of acute inflammatory mediators, especially eicosanoids (prostaglandins, leukotrienes), due to the production of Lipocortin, an enzyme that inhibits Phospholipase A2, preventing the formation of Arachidonic Acid and its metabolites.

Glucocorticoids also reduce the number of circulating immunocompetent cells (neutrophils and macrophages) and decrease the activity of cells involved in the chronic stages on inflammation (macrophages, fibroblasts), decreasing inflammation and decreasing healing.

44

How are glucocorticoids used in asthma?

Glucocorticoids provide a cornerstone for the longer-term management of chronic asthma and can be administered by inhalation and in severe cases orally or intravenously. They have both an anti-inflammatory action and increase the expression of β2 Receptors. Optimal effects are seen after weeks/months of therapy.

Cases of acute asthma often require oral steroids (typically 40mg Prednisolone) for 1-2 weeks along with inhaled therapy. Asthma presenting to A&E may require intravenous hydrocortisone to be given.

45

What are the pharmacokinetics of glucocorticoids in asthma?

10-50% of an inhaled dose is delivered to the lungs, depending on the inhaler device. A major proportion of the drug is deposited in the upper airway and/or swallowed and metabolised by the liver. Newer drugs are designed to undergo hepatic first pass metabolism to reduce ADR risk.

46

What treatment is given in Mild Intermittent Asthma

Inhaled short acting β2 Agonist as required (E.g. Salbutamol)

47

What treatment is given in step 2 (Introduction of regular preventer therapy)